Amine derivatives containing a phosphonic acid moiety

ABSTRACT

This invention concerns compounds of formula (I) wherein E represents hydrogen, C 1  -C 6  alkyl or a group Ar 1  -A 1  ; Ar and Ar 1  when present each represent an aryl group of 6 to 10 carbon atoms or a heteroaryl group of 5 to 10 ring atoms wherein the heteroatoms are selected from oxygen, nitrogen and sulphur, which may be optionally substituted by one or more substituents selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cyano, amino, mono- or di-(C 1  -C 6 ) alkylamino, hydroxy and nitro; A and A 1  when present are the same or different alkylene groups having one or two carbons linking Ar or Ar 1  to N, each optionally substituted by alkyl of 1 to 6 carbon atoms or an optionally substituted Ar group as defined above, B is a straight chain alkylene group of 3 or 4 carbon atoms optionally substituted by alkyl of 1 to 6 carbon atoms, and 
     D represents one of the following ##STR2## where R 1  and R 2  are independently hydrogen, alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 12 carbon atoms; R 3  is --CH(Oalkyl) 2  in which the alkyl group contains 1 to 6 carbon atoms and R 4  is alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 12 carbon atoms, which compounds are GABA autoreceptor agonists useful as antidepressants and for treating senile dementia.

This application was filed under 35 U.S.C. § 371 and was based upon PCTInternational Application No. PCT/GB92/02229 which was filed on Dec. 1,1992.

This invention relates to amines possessing a pharmacological activity,to processes for preparing them and to pharmaceutical compositionscontaining them. More particularly this invention relates to aminesuseful in the treatment of depression.

In the UK the annual referral rate for depression is around 300-400 per10⁵ population of whom 10-15% require hospitalisation. At present themost effective and safe treatment for severe depression involveselectroconvulsive therapy (ECT) where the patient receives a series ofcontrolled electric shocks. However such treatment understandablyengenders an atavistic fear and apprehension in many patients. It alsohas undesirable side-effects, notably disturbance of memory.

ECT is also expensive and time-consuming to administer, requiring thepresence of specialist doctors such as psychiatrists and anaesthetists.As an alternative to ECT, drug therapy provides a more acceptabletreatment for the patient but at the present time such therapy has notdisplaced ECT as the optimal treatment in severe cases because it is notalways effective. There is therefore a need for new drugs for thetreatment of depression, especially drugs having new modes of actionmimicking ECT.

The mode of action of ECT remains unknown but in recent years much hasbeen learnt about the biological effects of electroconvulsive shock(ECS) in animals. In particular, repeated ECS, given in ways closelymimicking those used to administer ECT clinically, elicits in rodentschanges in monoamine functions. These include: increased 5-HT-mediatedbehaviour, increased dopaminergic behaviour and depressedbeta-adrenoceptor binding and sensitivity of the coupled adenylatecyclase. The last is also seen following chronic treatment with a numberof antidepressant drugs.

The effects of repeated ECS are presumably a response or adaptation tothe acute effects of the seizures. Among these acute effects are amarked change in the release, synthesis and level of gamma aminobutyricacid (GABA) in the brain.--see Green A. R. et al, British J. Pharmacol.,92, 5-11 and 13-18 (1987) and Bowdler et al, ibid, 76, 291-298 (1982).

GABA is one of the most widespread and abundant transmitters in themammaltan central nervous system and plays a major role in the controlof brain excitability. It is similarly implicated in thebenzodiazepine-mediated relief of anxiety. Recently, evidence has cometo light which suggests that GABA transmission may also be involved inthe therapeutic effects of some antidepressant treatments. Inparticular, new compounds designed as GABA agonists (e.g. fengabine andprogabide) have been shown in preliminary clinical trials to haveantidepressant activity (vide infra). Taken together, these findingssuggest that interventions directed specifically at GABA transmissionmay provide the basis of novel therapies for the treatment of affectivedisorders.

At present three GABA receptors have been identified in the centralnervous system. These are (1) a GABA_(A) -receptor known to be mainlypostsynaptic and mediating inhibition of neuronal firing--see forexample Stephenson, F. A. Biochem, J., 249 pp 21-32 (1988); (2) aGABA_(B) receptor located both postsynaptically and presynaptically,where it mediates the inhibition of release of a number ofneuro-transmitters, e.g. noradrenaline and aspartic acid,--see forexample Bowery, N. G. et al, Nature, 283, 92-94 (1980); and (3) a GABAautoreceptor which modulates the release of GABA from neurones--see forexample Mitchell, P. R., and Martin, I. L. Nature, 274 904-905 (1978);Arbilla, S. Kanal, J. L and Langer, S. Z. Eur.J.Pharmac., 57, 211-217(1979) and Brennan M. J. W. et al, Molec. Pharmac., 19, 27-30 (1981).

The pharmacological importance of these receptors is currently a subjectof investigation with a major part of the work involving the search foranticonvulsant drugs with a mode of action involving GABA_(A) receptors.Two drugs acting on GABA receptors, progabide and fengabine, have alsobeen shown to possess antidepressant effects in preliminary clinicaltrials--see P. L. Morselli et al, L.E.R.S. Vol 4 (1986) pp 119-126 andB. Scatton et al, Journal of Pharm. and Exp. Therapeutics., 241, 251-257(1987). The latter workers showed that fengabine possessed a biochemicalmode of action different from that of conventional antidepressants butthat the mechanism whereby fengabine exerted its antidepressant actionswas not yet clear. It was thought to derive from a GABAergic action,most likely at GABA_(A) receptors.

In the case of progabide, Morselli et al also attributed theantidepressant effect to an increased GABAergic transmission.

In copending UK patent publication No 2219295B evidence is provided thatthe antidepressant effect of progabide and fengabine is in fact due totheir agonist action at the GABA autoreceptor.

The GABA autoreceptor is capable of regulating the release of GABA fromGABAergic neurons which means an agonist at the autoreceptor woulddecrease the GABA release hence decreasing GABA function ie. an actionopposite to that of GABA_(A) agonists. Previously the autoreceptor wasbelieved to have the same pharmacology as the GABA_(A) site--see Molec.Pharm, 19, 27-30 (1981). We have found that the GABA autoreceptor hasits own distinct pharmacology and that there are compounds havingselective agonist activity at the GABA autoreceptor. These compoundshave valuable medical uses.

There is also evidence that compounds acting at the benzodiazepinereceptor as inverse agonists decrease GABA function in the brain andthus increase acetylcholine transmission. In addition, probably as aconsequence of these actions, they facilitate memory in animals and man(see Sarter. M. et al. Trends in Neuroscience, 11 13-17, 1988).Compounds acting as GABA autoreceptor agonists are believed to havesimilar actions such as nootropic activity (e.g. increased vigilance andcognition) and are therefore useful in the treatment of cerebralinsufficiency disorders and dementias.

Accordingly this invention provides a compound having formula: ##STR3##or a salt thereof,wherein E represents hydrogen, lower alkyl or a groupAr¹ -A¹ -; Ar and Ar¹ are the same or different aryl groups (includingheteroaryl) which are optionally substituted, e.g. by one or moresubstituents the same or different commonly used in pharmaceuticalchemistry such as lower alkyr, lower alkoxy, halogen, haloloweralkyl,haloloweralkoxy, cyano, amino (including substituted amino eg. mono- ordi-loweralkyl amino), hydroxy and nitro; A and A¹ when present areindependently an alkylene group having one or two carbon atoms linkingAr or Ar¹ to N, which group is optionally substituted by lower alkyland/or optionally substituted aryl (including heteroaryl), B is astraight chain alkylene group of 3 or 4 carbon atoms, which may besubstituted by lower alkyl; D represents --P(═O)(OR¹)(OR²) where R¹ andR² are independently hydrogen, loweralkyl or C₇ -C₁₂ aralkyl;--P(H)(═O)(OH) or --P(═O)(R³)(OR⁴) where R³ is CH(O alkyl)₂ and R⁴ isloweralkyl or C₇ -C₁₂ aralkyl.

By the term "lower" is meant a group containing 1 to 6 carbon atoms,preferably 1 to 4 carbon atoms. Examples of lower alkyl are methyl,ethyl, propyl and butyl.

Examples of R¹ and R² include hydrogen, methyl, ethyl, propyl and butyland aralkyl groups of 7 to 12 carbon atoms e.g. benzyl, 2-phenethyl.

Examples of R³ are CH(Oloweralkyl)₂ such as CH(OMe)₂, CH(OEt)₂ orCH(OPr)₂.

Examples of R⁴ are methyl, ethyl, propyl and butyl and aralkyl groups of7 to 12 carbon atoms e.g. benzyl or 2 -phenethyl.

Examples of Ar and Ar¹ are mono- or bi-cyctic aryl groups such ascarbocyclic aryl groups of 6 to 10 carbon atoms (e.g. phenyl ornaphthyl) and mono- or bi-cyclic heteroaryl groups of 5 to 10 fine atomsin which the heteroatom is selected from oxygen, nitrogen and sulphur(e.g. furan, pyridine, thioohene) or aromatic groups containing two ormore such heteroatoms (e.g. thiazolyl). Bicyclic heteroaryl groups areexemplified by quinoline (e.g. quinol-6-yl, quinol-2-yl) and benzofuran(e.g. benzofuran-2-yl).

Examples of A and A¹ are independently --(CH₂)_(m) -- optionallysubstituted by lower alkyl and/or aryl where m is 1 or 2. Preferably Aand A¹ are independently --CHR⁸ -- where R⁸ is hydrogen, lower alkyl,eg. methyl or ethyl, or optionally substituted aryl or heteroaryl asdefined for Ar, e.g. phenyl. Examples of B are --CH₂ CH₂ CH₂ -- and sucha group substituted by lower alkyl such as methyl, e.g. B represents--CH(CH₃)CH₂ CH₂ -- or --CH₂ CH(CH₃)CH₂ --.

Examples of substituents on Ar, Ar¹ and R⁸ when aryl or heteroaryl areone or more of the following methyl, ethyl, propyl, butyl, methoxy,ethoxy, n-propoxy, n-butoxy, fluorine, chlorine, bromine, chloromethyl,chloroethyl, trifluoromethyl, trifluromethoxy, cyano, amino,methylamino, ethylamino, n-propylamino, hydroxy, dimethylamino,diethylamino, methylethylamino and nitro.

The compounds of formula I as defined above possess pharmacologicalactivity especially activity affecting the nervous system. In particularthe compounds of formula I are inhibitors of gamma aminobutyric acid(GABA) release from nerve terminals via action on the GABA autoreceptor.

The compounds of formula I demonstrate activity at GABA autoreceptorsmore specifically they demonstrate agonist activity as shown by standardin vitro test procedures. The following test procedures were used tomeasure activity at (a) GABA autoreceptors and GABA_(B) receptors byinhibition of potassium-evoked GABA and noradrenalin release from ratcortex in vitro (Procedure 1):

Procedure (1)

Slices (0.25×0.25×2.0 mm) of rat cerebral cortex are prepared using aMcI]wain tissue chopper. The slices are incubated in Krebs-Henseleitsolution containing [³ H]-GABA (10⁻⁷ M) and [¹⁴ C]-noradrenaline (10⁻⁷M) in the presence of amino-oxyacetic acid (AOAA) (10⁻⁵ M), pargyline(10⁻⁶ M) and ascorbic acid (10⁻⁴ M), for 20 minutes at 37° C., rinsedwith 5 ml aliquots of Krebs-Henseleit solution and transferred to 10superfusion chambers (volume 300 μl). The slices are continuouslysuperfused with Krebs-Henseleit solution (0.4 ml min⁻¹) containing AOAA(10⁻⁵ M) and fractions of the superfusate collected every 4 minutes.Transmitter release is induced by 4 minute exposure to a Krebs-Henseleitsolution containing 25 mM potassium (with concomitant reduction insodium to maintain osmolarity) after 68 (S₁) and 92 (S₂) minutes ofsuperfusion. The compound under study is added to the superfusing medium20 minutes prior to the second potassium stimulation. The residualradioactivity in the slices at the end of the experiment together withthat in the superfusate fractions is measured by liquid scintillationcounting using a dual label programme for tritium and carbon-14.

Calculations

The amount of radioactivity (either tritium or carbon-14) in eachfraction is expressed as a percentage of the respective totalradioactivity in the tissue at the start of the respective collectionperiod. The amount of radioactivity released above basal by theincreased potassium is calculated and the ratio S2/S1 obtained. TheS2/S1 ratio from drug-treated slices is expressed as a percentage of thecontrol S2/S1 ratio. For compounds achieving inhibition of 30% or morepD₂ values are calculated from plots of inhibition of release versusconcentration of drug. Failure to inhibit the release of noradrenalineindicates that the molecule has no GABA_(B) agonist activity.

RESULTS

In the aforementioned test the following representative compound gavethe result shown:

    ______________________________________                                                        GABA autoreceptor                                                                           Inhibition of                                                   Inhibition of release of                                                      release of    noradrenaline                                   Compound        GABA at 10.sup.-5 M                                                                         at 10.sup.-5 M                                  ______________________________________                                        3-[N,N-bis-(4-Chlorobenzyl)-                                                                  17%           17%                                             amino]propylphosphonic acid                                                   ______________________________________                                    

In another aspect this invention provides use of a compound of formula Ifor the preparation of a medicament for the treatment of senile dementiaand/or depression.

This invention also provides processes for preparing the compounds ofthe invention.

Compounds of formula I may be prepared by any one of the followingprocesses:

a) alkylating a compound of formula II, IIa or IIb

    Ar-A-NH-E                                                  II

    Ar-A-NH-B-D.sup.1                                          IIa

    E-NH-B-D.sup.1                                             IIb

wherein Ar, E and A are as defined above and D¹ is --P(O)(R³)(OR⁴) whereR³ and R⁴ are as defined above or --P(O)(OR⁵)(OR⁶) in which R⁵ and R⁶independently represent loweralkyl or C₇ -C₁₂ aralkyl with anappropriate compound of formula III; IIIa or IIIb:

    hal-B-D.sup.1                                              (III)

    E.sup.1 -hal                                               (IIIa)

    Ar-A-hal                                                   (IIIb)

wherein D¹, B, Ar and A are as defined above, hal represents chlorine orbromine, and E¹ is E is defined above excepting hydrogen, to give acompound of formula I wherein R¹ and R² indpendently represent loweralkyl or C₇ -C₁₂ aralkyl or R³ and R⁴ are as defined above; or

b) carrying out a reductive alkylation of a compound of formula II, IIaor IIb as defined above using an appropriate compound of formula IV, IVaor IVb

    OHC-B.sup.1 -D.sup.1                                       (IV)

    OHC-E.sup.2                                                (IVa)

    OHC-A.sup.2 -Ar                                            (IVb)

wherein D¹ is as defined above, E² is alkyl of 1 to 5 carbon atoms orAr¹ --CH₂ -- wherein Ar¹ is as defined above, A² is CH₂ and B¹ is analkylene chain of 2 or 3 carbon atoms optionally substituted by loweralkyl, in the presence of a reducing agent such as sodiumcyanoborohydride to give a corresponding compound of formula I wherein

R¹ and R² independently represent lower alkyl or C₇ -C₁₂ aralkyl or R³and R⁴ are as defined above; or

(c) reducing a compound of formula (V) ##STR4## wherein D¹ is as definedabove, R⁷ is alkyl of 1 to 5 carbon atoms or Ar¹ -A² -; Ar, Ar¹, A and Bare as defined above, and A² represents a direct bond or alkylene of 1carbon atom optionally substituted by lower alkyl and/or an optionallysubstituted Ar group wherein Ar is as defined above, to give acorresponding compound of formula I as defined above wherein R¹ and R²independently represent lower alkyl or C₇ -C₁₂ aralkyl and E is R⁷ CH₂wherein R⁷ is as defined above; or

(d) reducing a compound of formula (VI) ##STR5## wherein Ar, A and E areas defined above, D¹ is as defined above and B¹ is as defined inconnection with formula IV to give a corresponding compound of formula Iwherein B is --CH₂ B¹ -- or

e) reacting a compound of formula ##STR6## wherein Ar,- A, B and E areas defined above and L represents a leaving group, e.g. a halogen suchas chlorine or bromine, or an organic sulphonyloxy group such as analkyl or aryl-sulphonyloxy group, e.g. methane- or toluene-sulphonyloxy,with a compound of formula:

    (i) P(OR).sub.3                                            (VIII)

wherein R is lower alkyl or C₇ -C₁₂ aralkyl, or ##STR7## wherein R³, R⁴,R⁵ and R⁶ are as defined above to give a corresponding compound offormula I, or

f) converting an ester of formula I wherein D is --P(O)(OR¹)(OR²)wherein at least one of R¹ and R² is lower alkyl or C₇ -C₁₂ aralkyl, or--P(O) (R³) (OR⁴) to a corresponding compound of formula I wherein D isP(O)(OR¹)(OR²) wherein R¹ and R² are both hydrogen or one is lower alkylor C₇ -C₁₂ aralkyl, or P(H)(═O)(OH), or

g) reducing a compound of formula ##STR8## wherein Ar, A², E, B and D¹and as defined above, to give a corresponding compound of formula Iwherein A is --A² CH₂ --.

With regard to process (a) the reaction may be conveniently carried outin the presence of an inert solvent and a base such as a tertiary amine(e.g. diisopropylethylamine) with heating if required. Examples ofsuitable inert solvents are dimethylformamide, acetonitrile anddimethylsulphoxide.

With regard to process (b) the reductive alkylation is convenientlycarried out in an inert solvent, depending on the reducing agent, andwithout heating. When the reducing agent is sodium cyanoborohydride thesolvent may be an aqueous alcohol such as aqueous ethanol. Catalytichydrogenation may also be used. e.g. using Pd/C and an alcohol solvent,eg. ethanol.

Process (c), (d) and (g) may be carried out using a P₂ S₅ and Raneynickel reduction. Process e) (i) may be carried out under conditionssuitable for the Arbuzov reaction. With regard to process e) (ii) andprocess e) (iii) the anion of the compounds of formulae IX and X may begenerated using sodium hydride. Process (f) may be carried out bycomplete or partial hydrolysis (using acid or base catalysis); estercleavage (e.g. using trimethyl silylbromide or iodide) or hydrogenation(to remove R¹ and/or R² when benzyl, e.g. using Pd/C).

The starting materials of formula II used in process (a) are knowncompounds or can be prepared by analogous methods e.g. by reducing anamide of formula Ar-A-NHCO-E¹ where E¹ has one CH₂ group less than E.Compounds of formula V can be prepared by acylating a correspondingcompound of formula Ar-A-NH-B-D¹ using an acid chloride of formula R⁷COCl. Compounds of formula Ar-A-NH-B-D¹ can themselves be prepared byalkylating amines of formula NH₂ -B-D¹ using a halide of formulaAr-A-hal.

Compounds of formula XI can be prepared by acylating an amine of formulaHN(E)BD¹ using an acid chloride of formula ArA² COCl.

Compounds of formula VI can be prepared by acylating amines of formulaAr-A-NH-E using an acid chloride of formula ClCO.B¹ -D¹ wherein B¹ hasthe value defined in connection with process (d).

Starting materials for the processes described herein are knowncompounds or can be prepared by analogous methods for known compounds.

In any of the aforementioned reactions compounds of formula I may beisolated in free base form or as acid addition salts as desired.Examples of such salts include salts with pharmaceutically acceptableacids such as hydrochloric, hydrobromic, hydroiodic, sulphuric,phosphoric, nitric, acetic, citric, tartaric, fumaric, succinic,malonic, formic, maleic acid or organosulphonic acids such as methanesulphonic or tosylic acid.

When acidic substituents are present it is also possible to form saltswith strong bases, e.g. those of alkali metals (such as sodium orpotassium). Such salts of the compounds of formula I are included withinthe scope of this invention.

This invention also provides pharmaceutical compositions comprising acompound of formula I or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable carrier.

For the pharmaceutical compositions any suitable carrier known in theart can be used. In such a composition, the carrier may be a solid,liquid or mixture of a solid and a liquid. Solid form compositionsinclude powders, tablets and capsules. A solid carrier can be one ormore substances which may also act as flavouring agents, lubricants,solubilisers, suspending agents, binders, or tablet disintegratingagents; it can also be encapsulating material. In powders the carrier isa finely divided solid which is in admixture with the finely dividedactive ingredient. In tablets the active ingredient is mixed with acarrier having the necessary binding properties in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from 5 to 99, preferably 10-80% of the activeingredient. Suitable solid carriers are magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low melting wax and cocoa butter. Theterm "composition" is intended to include the formulation of an activeingredient with encapsulating material as carrier, to give a capsule inwhich the active ingredient. (with or without other carrier) issurrounded by carriers, which is thus in association with it. Similarlycachets are included. Sterile liquid form compositions include sterilesolutions, suspensions, emulsions, syrups, and elixirs.

The active ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such a sterile water, sterileorganic solvent or a mixture of both. The active ingredients can oftenbe dissolved in a suitable organic solvent, for instance aqueouspropylene glycol containing from 10 to 75% of the glycol by weight isgenerally suitable. Other compositions can be made by dispersing thefinely-divided active ingredient in aqueous starch or sodiumcarboxymethyl cellulose solution, or in a suitable oil, for instancearachis oil. The composition may be administered orally, nasally,rectally or parenterally.

Preferably the pharmaceutical composition is in unit dosage form, thecomposition is sub-divided in unit doses containing appropriatequantities of the active ingredient; the unit dosage form can be apackaged composition, the package containing specific quantities ofcompositions, for example packeted powders or vials or ampoules. Theunit dosage form can be a capsule, cachet or tablet itself, or it can bethe appropriate number of any of these in packaged form. The quantity ofactive ingredient in a unit dose of composition may be varied oradjusted from 1 to 500 mg or more, e.g. 25 mg to 250 mg, according tothe particular need and activity of the active ingredient. The inventionalso includes the compounds in the absence of carrier where thecompounds are in unit dosage form. Based on the results from animalstudies the dosage range for the treatment of humans using a compound offormula I will be in the range from about 1 mg to 2 g per day dependingon the activity of the compound.

Compounds of formula I wherein at least one of R¹ and R² are lower alkylor aralkyl, or R³ and R⁴ are as defined above are intermediates tocompounds of formula I wherein D is --PO₃ H₂ or --PO₂ H₂.

The following Examples illustrate the invention and methods forpreparing compounds of the invention.

EXAMPLE 1 3-[N,N-bis-(4-chlorobenzyl)amino]propylphosphonic acid diethylester

a) 3-[N,N-bis-(4-chlorobenzyl)amino]propyl chloride was prepared byhalogenating 3-[N,N-bis-(4-chlorobenzyl)amino]propanol using thionylchloride.

b) 3-[N,N-bis-(4-chlorobenzyl)amino]propyl chloride (1.8 g 0.0054 moles)was dissolved in diethyl phosphlte (10 ml, large excess). Sodium hydride(2 g, excess) was added, then the mixture heated to 160° C. for 18hours. After cooling the mixture was taken up into brine (50 ml) and theproduct extracted into chloroform (3×50 ml), then dried (MgSO₄). Excesstriethyl phosphate was distilled out of the mixture at 150° C., 20 mmHgto give the title compound (1.7 g). infra red (liquid) strong broadbonds at 1241, 1090, 1050, 1020 and 965 cm⁻¹.

EXAMPLE 2 3-[N,N-bis-(4-Chlorobenzyl)amino]propyl phosphonic acid

3-[N,N-bis-(4-chlorobenzyl)amino]propyl phosphonic acid diethyl ester(prepared according to Example 1) was dissolved in 8N HCl (25 ml), thena small amount of isopropyl alcohol added to effect solution. Afterheating for 6 hours, evaporation gave the title compound as a glass.

Infra red (nujol mull): Sharp peaks at 1090 and 1016 cm⁻¹ on abackground in 900-1250 cm⁻¹ region.

This was purified by crystallisation from hot water to give thedihydrate of the title compound, top. 161°-165° C.

C₁₇ H₂₀ Cl₂ NO₃ P.2H₂ O requires: C,48.1; H,5.7: N,3.3% Found : C,48.0;H,5.9; N,3.2%

EXAMPLES 3-5

In a similar manner to Examples 1 and 2 the following phosphonouscompounds of formula A prepared according to the reaction

    ______________________________________                                         ##STR9##                                                                      ##STR10##                                                                    wherein:                                                                      Example No Ar           A      E                                              ______________________________________                                        3          1-naphthyl   CH.sub.2                                                                             CH.sub.3                                       4          4-chlorophenyl                                                                             CH.sub.2                                                                             CH.sub.3                                       5          1-naphthyl   CH.sub.2                                                                             1-naphthylmethyl                               ______________________________________                                    

EXAMPLES 6-8

In a similar manner to Examples 1 and 2 the following phosphoniccompounds of formula B are prepared according to the reaction

    ______________________________________                                         ##STR11##                                                                     ##STR12##                                                                    wherein                                                                       Ex No Ar          A      E          Melting Point                             ______________________________________                                        6     1-naphthyl  CH.sub.2                                                                             CH.sub.3   --                                        7     4-chlorophenyl                                                                            CH.sub.2                                                                             CH.sub.3   --                                        8     1-naphthyl  CH.sub.2                                                                             1-naphthylmethyl                                                                         145-160° C.*                       ______________________________________                                         *as the monohydrochloride, quarterhydrate salt                           

We claim:
 1. A compound of formula ##STR13## wherein E representshydrogen, C₁ -C₆ alkyl or a group Ar¹ -A¹ ;Ar and Ar¹ when present each,independently, represent an aryl group which is phenyl or naphthyl or amono- or bi-cyclic heteroaryl group of 5 to 10 ring atoms wherein theheteroatoms are selected from oxygen, nitrogen and sulphur, which may beoptionally substituted by one or more substituents selected from alkylof 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen,haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms,cyano, amino, mono- or di-(C₁ -C₆)alkylamino, hydroxy and nitro; A andA¹ when present are the same or different alkylene groups having one ortwo carbons linking Ar or Ar¹ to N, each optionally substituted by alkylof 1 to 6 carbon atoms or an optionally substituted Ar group as definedabove, B is a straight chain alkylene group of 3 or 4 carbon atomsoptionally substituted by alkyl of 1 to 6 carbon atoms, and D represents##STR14## where R¹ and R² are independently hydrogen, alkyl of 1 to 6carbon atoms or aralkyl of 7 to 12 carbon atoms; with the proviso that,when B is a propylene group optionally substituted by one lower alkylgroup, Ar-A- does not represent unsubstituted aralkyl.
 2. A compound asclaimed in claim 1 in which A and A¹ when present are independently agroup of formula --CHR⁸ -- where R⁸ is hydrogen, alkyl of 1 to 4 carbonatoms or a phenyl, naphthyl, or mono- or bi-cyclic heteroaryl group inwhich the heteroatoms are selected from oxygen, nitrogen and sulphur,said group optionally substituted as defined for aryl or heteroaryl inclaim
 1. 3. A compound as claimed in claim 2 in which the optionalsubstituents on the Ar, Ar¹ or R⁸ group are independently selected fromone or more of the following: methyl, ethyl, propyl, butyl, methoxy,ethoxy, n-propoxy, n-butoxy, fluorine, chlorine, bromine, chloromethyl,chloroethyl, trifluoromethyl, hydroxy, trifluoromethoxy, cyano, amino,methylamino, ethylamino, n-propylamino, dimethylamino, diethylamino,methylethylamino and nitro.
 4. A compound as claimed in claim 1 whereinB is --(CH₂)₃ -optionally substituted by methyl.
 5. A compound asclaimed in claim 1 wherein R¹ and R² are the same or different and eachrepresent hydrogen, methyl, ethyl, propyl, butyl, benzyl or 2-phenethyl.6. A compound as claimed in claim 1 when in the form of(a) a salt of anacid selected from hydrochloric, hydrobromic, hydroiodic, sulphuric,phosphoric, nitric, acetic, citric, tartaric, fumaric, succinic,malonic, formic, maleic, methanesulphonic and tosylic acid, or (b) whenan acidic group is present, the sodium or potassium salt. 7.3-[N,N-bis-(4-Chlorobenzyl)amino]proplphosphonic acid diethyl ester. 8.3-[N,N-bis-(4-Chlorobenzyl)amino]propylphosphonic acid.
 9. Apharmaceutical composition comprising a compound of formula I as definedin claim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 10. A method of treating depressionor memory impairment disorders or dementias in a mammal so afflicted,comprising administering to said mammal an amount effective to alleviatedepression or memory impairment or dementia of a compound of formula##STR15## wherein E represents hydrogen, C₁ -C₆ alkyl or a group Ar¹ -A¹;Ar and Ar¹ when present each, independently, represent an aryl groupwhich is phenyl or naphthyl or a mono- or bi-cyclic heteroaryl group of5 to 10 ring atoms wherein the heteroatoms are selected from oxygen,nitrogen and sulphur, which may be optionally substituted by one or moresubstituents selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of1 to 6 carbon atoms, cyano, amino, mono- or di-(C₁ -C₆)alkylamino,hydroxy and nitro; A and A¹ when present are the same or differentalkylene groups having one or two carbons linking Ar or Ar¹ to N, eachoptionally substituted by alkyl of 1 to 6 carbon atoms or an optionallysubstituted Ar group as defined above, B is a straight chain alkylenegroup of 3 or 4 carbon atoms optionally substituted by alkyl of 1 to 6carbon atoms, and D represents ##STR16## where R¹ and R² areindependently hydrogen, alkyl of 1 to 6 carbon atoms or aralkyl of 7 to12 carbon atoms; or a pharmaceutically acceptable salt thereof,with theproviso that, when B is a propylene group optionally substituted by onelower alkyl group, Ar-A- does not represent unsubstituted aralkyl.
 11. Amethod of treating depression or memory impairment disorders ordementias wherein Ar-A- and Ar¹ -A¹ - of the compound of formula I asclaimed in claim 10 are the same.
 12. A method of treating depression ormemory impairment disorders or dementias wherein the compound of formulaI as claimed in claim 10 is in the form of(a) a salt of an acid selectedfrom hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric,nitric, acetic, citric, tartaric, fumaric, succinic, malonic, formic,maleic, methanesulphonic and tosylic acid, or (b) when an acidic groupis present, the sodium or potassium salt.
 13. A method of treatingdepression or memory impairment disorders or dementias wherein thecompound of formula I as claimed in claim 10 is3-{N,N-bis-(4-chlorobenzyl)amino)propyl phosphonic acid or the diethylester thereof.